Meldrum’s acid assisted formation of tetrahydroquinolin-2-one derivatives a short synthetic pathway to the biologically useful scaffold

A new method for the preparation of tetrahydroquinolin-2-one derivatives is presented. This approach involves a two-step reaction between enaminones and acylating agents, immediately followed by electrophilic cyclization, all within a single synthesis procedure, eliminating the need to isolate intermediates. The entire process is facilitated by the use of acyl Meldrum’s acids which not only shortens the preparation time of the substrates but also easily extends the range of substituents That can be used. The method’s scope and limitations were evaluated with various reagent combinations thus demonstrating its general applicability to the synthesis of tetrahydroquinolin-2-one core. Interestingly, some exceptions to the regular reaction pathway were observed when a strong EDG (electron donating group) was introduced via acyl Meldrum’s acids. The underlying mechanism of this phenomenon was elucidated during the investigation.

1,3 dicarbonyl derivatives.Sheibani and co-workers published a paper where they described the reaction of an enamine conjugated with carbonyl reacts with (chlorocarbonyl)phenyl ketene 20 .A somewhat similar approach was used by Guillemont and co-workers, who detailed the formation of the 2-pyridone scaffold in the reaction of a conjugated enamine with an activated malonic derivative 21 .A completely different approach assumes the application of methyl propiolate with enaminone 22,23 .The method using methoxymethylene Meldrum's acid and enaminone also deserves mention 24,25 .
The method previously used in our laboratory for the synthesis of the tetrahydroquinolin-2-one scaffold 10,11 was a combination and adaptation procedures described by several research groups [26][27][28] .However, due to difficulties with the direct procedure involving benzoyl acetate, ammonium acetate, and cyclohexanone, where the in-situ formation of an amide was expected, followed by subsequent reaction with cyclohexanone, we opted to synthesize the amide separately, isolate it, and then proceed to condense the 1,3-dicarbonyl amide with cyclohexanone to obtain the desired 2-pyridone fused with a six-membered ring.Although this method was successful, it proved to be tedious and time-consuming in practice, prompting our search for an improved method for the preparation of a 2-pyridone scaffold.

Results and discussion
In this current paper, using our experience in synthesizing pyridones along with our knowledge about the applications of Meldrum's acid [29][30][31][32][33][34] in synthesis, and considering the available literature, we would like to introduce a new approach for the preparation of 2-pyridones.
Taking into account our past experience, we identified a key step to be obtaining a 1,3-dicarbonyl amide with an already attached fragment that allows cyclization, resulting in a 2-pyridone fused with a hexagonal ring, like the tetrahydroquinolin-2-one.The enamide 11 in Fig. 3 aligns with these criteria.At this stage, we assumed that such an enamide would readily undergo the desired cyclization under acidic conditions.
In theory, obtaining the appropriate enamide should be straightforward with the enaminone and acylating reagent being available.However, using acyl-acetate esters is not recommended due to their low reactivity with amino groups and potential side reactions with the ketone fragment.However, the use of strong acylating reagents like chlorides, anhydrides, or ketenes, as seen in cited works [18][19][20][21] , presents challenges in preparation and storage.This led us to consider exploiting the acylating properties of Meldrum's acid derivatives, which would allow us to introduce 1,3-dicarbonyl moiety together with the possibility of introducing a broad scope of side chains.It should be noted that the used acyl derivatives of Meldrum's acid are stable compounds, easily purified and prepared from commercially available starting materials.
We conducted two experiments with the cyclization of enamide 11aa in the presence of PPA.The first, carried out in boiling dichlorobenzene (DCB) for 2 h, resulted in the formation of compound 12aa with a 37% yield, while the second was performed in boiling dichloroethane (DCE) within 6 h, yielding 34% (Fig. 4).
With these outcomes, we explored the possibility of conducting both the intermolecular and intramolecular processes without the isolation of the enamide intermediate in a "one-pot" reaction.To test this hypothesis, we initiated the condensation of a fourfold excess of benzoyl Meldrum's acid 9a with enaminone 10a.Once the enamide formation was complete and the disappearance of benzoyl Meldrum acid was confirmed through TLC analysis, PPA was introduced to the reaction, and the entire mixture was heated to its boiling point for 6 h.This resulted in the formation of product 12aa with a yield of 32% (Fig. 5).As an alternative to the use of PPA we tested TsOH in toluene; however, this resulted in a weaker outcome since the yield after both steps combined was only 15%.
Encouraged by these findings, we decided to perform a series of reactions using various derivatives of Meldrum's acid and enaminones to evaluate the scope and limitations of this newly developed method.With our new method, we were able to prepare a wide range of compounds efficiently with a 7,8-dihydroquinoline-2,5(1H,6H)dione scaffold in a single laboratory step, achieving moderate yields (Table 1).
In the case of 5-(1-hydroxy-2-(naphthalen-1-yl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9f) used as a Meldrum's acid (Table 1, Run 9), enamide formation was observed but subsequent condensation using PPA was unsuccessful.A similar situation arose when 3-aminocyclopent-2-enone was applied.Surprisingly, when derivative 9c was used as a Meldrum's component (Table 1, Run 3), a notably different product compared to the other results was isolated from the reaction mixture.Determining the structure of this unexpected product was an essential step in our analysis.In became evident that this compound contained a double fragment originating   www.nature.com/scientificreports/from the Meldrum derivative and only one from the enaminone.Based on data from NMR and MS, we proposed the following structure, which may exist in equilibrium with its keto form (Fig. 6).This prompted us to investigate the reaction mechanism behind this particular outcome.First, we sought to determine the step in the process that was responsible for the formation of this unusual product.Since the unexpected product contained an "excess" of moieties originating from acyl Meldrum's acid, it suggested that the surplus of compound 9c used in a "one-step" process might be causing this atypical reaction course.To test this, we prepared enamide 11ca following the stepwise procedure, and isolated and purified it.In the next step, we attempted to cyclize purified 11ca using PPA.This reaction again yielded compound 13ca with a 21% yield (Fig. 7).
The result confirmed that the excess of acyl Meldrum's acid used in the "one-pot" reaction wasn't responsible for the unusual course of the reaction.Compound 13ca seemed to be formed through the interaction of two molecules of enamide 11ca.To explain the formation of product 13ca we proposed a tentative reaction mechanism presented in Fig. 8A.
Obviously, we paid attention to the fact that only the reaction of p-methoxy derivative of Meldrum's acid with dimedone enaminone gave us an unexpected product.Thus, to explain this phenomenon, we hypothesized that EDG caused a decrease in the electrophilicity of the keto carbonyl carbon in enamide 11ca.This inhibited preferred intramolecular cyclization process (Fig. 8B) which would typically lead to the usual product 12ca and simultaneously enabled the observation of a more entropically challenging intermolecular process.To validate our hypothesis, we decided to obtain and purify enamide 11ga with a furyl substituent possessing a strong M+ effect (Fig. 9a).Subsequently, we carried out the intramolecular condensation with PPA once again, resulting in the formation of compound 13ga which confirmed that an EDG indeed affects the course of the reaction (Fig. 9b).
In both intermolecular (Fig. 8A) and intramolecular (Fig. 8B) reactions, the enaminone fragment plays the role of the nucleophile, with the largest contribution to the HOMO orbital of the molecule.In the discussed intermolecular condensation, it is theoretically possible for the nucleophile to attack either the keto-carbonyl (not shown in Fig. 8A) or the amide carbonyl carbon atom.Considering the factors affecting the transition of the reaction from intramolecular to intermolecular (the presence of ED group decreases the electrophilicity of keto-carbonyl carbon atom) it is likely that the enaminone nucleophile initiates the reaction with the amide carbonyl, as otherwise, we would observe with intramolecular cyclization like in substrates 11aa-ad, ba, da, ea when a weak EDG or EWG (electron withdrawing group) is present, which implies higher electrophilicity of keto-carbonyl than amide carbonyl carbon atom.
Moreover, in our search for the most basic position of the molecule, we estimated pKa values for the conjugate acids of enamide 11ca and its enol form 11ca′ using the "Chemaxon pKa calculator" 42 .The calculated pKa values were 1.0 and 0.4, respectively (Fig. 10).
In an environment with an excess of PPA, these compounds will be predominantly in the protonated form.The protonated forms are more electrophilic than the non-protonated ones.When considering the participation of these two forms in the actual course of the reaction, the position of the keto-enol equilibrium of protonated and deprotonated forms should also be taken into account.Based on the 1 H NMR spectra for EDG-substituted enamides in a non-polar solvent, the enol form was negligibly small.Consequently the most electrophilic species in our reaction mixture would be the protonated enamide 11ca (Fig. 10), providing further support for our proposed mechanism.

Conclusion
In this paper, we introduced a "one-pot" reaction developed by our team for the synthesis of 4-phenyltetrahydroquinolone cores.This process involves an initial formation of an appropriate enamide as an intermediate, followed by its condensation with PPA.The presented method has significant advantages over previously used procedures 26,27 .The "one-pot" synthesis allows obtaining the desired tetrahydroquinolone core within several hours, in mild conditions, without the intermediate isolation.The yields of the proposed synthesis are higher than those previously published (e.g.12% 27 ; 18-21% in two steps 43 ; 16% in two steps, 27% 25 ).The condensation of Meldrum's acid derivatives with enaminones also allows the tetrahydroquinolone core functionalization in the 4-position with alkyl substituents, which was not possible before due to the difficulties of ethyl acetoacetate and its alkyl derivatives ammonolysis.Additionally, the presence of carbonyl carbon in the 5-position opens new possibilities for tetrahydroquinolone core modification.Nevertheless, the presented method does have its limitations.The reaction predominantly proceeds through intramolecular cyclization for enamides that lack strong EDG.In contrast, for those with ED groups, we observed an intermolecular condensation pathway.

General
Commercially available reagents were purchased from Sigma Aldrich or Acros and used without further purification.Acyl Meldrum's acids 9a-f and enaminones 10a-d were prepared according to literature procedures; 9a, 9b, 9c, 9f 44 , 9d, 9e 45 , 10a-d 46 .Analytical thin layer chromatography was performed on aluminum sheets of UV 254 Merck silica gel, and flash chromatography using SilicaFlash P60 silica gel (40-63 µm). 1 H and 13 C NMR spectra were recorded with Bruker Avance III HD 400 MHz or Varian Gemini 500 MHz and NMR chemic al shifts were reported in δ (ppm) using residual solvent peaks as standards, with the coupling constant J measured in Hz.High resolution mass spectra were recorded with an Agilent 6540 Q TOF system High resolution (HRMS) was recorded on Agilent 6540 QTOF.

General procedure for preparation of compounds 12aa-da, 13ga
A solution of enaminone 10a-d (0.5 mmol) in 5 ml of DCE and molecular sieves were placed in a round bottom flask with a stir bar and heated to 55 °C.Then 2 mmol of acyl Meldrum's acid 9a-f were added in 4 portions every 1 h.The formation of enamide was monitored by TLC.When the spot of enaminone was no longer observed 0.8 g of PPA was added.The reaction mixture was then heated to reflux, left for 6 h and after that DCE was evaporated.The residue was then suspended in water, cooled in the ice bath and neutralized with NaOH.Next, the resulting suspension was subjected to extraction with AcOEt and DCM.Organic layers were washed with brine and dried with anhydrous MgSO 4 The final product was isolated by flash column chromatography (C:M 200:1 and if needed A:H 2:1).

General procedure for preparation of compounds 11aa-ga
A solution of dimedone enaminone 10a (0.5 mmol) in 5 ml of DCE and molecular sieves were placed in a round bottom flask with a stir bar and heated to 55 °C.Then 2 mmol of acyl Meldrum's acid 9a-g were added in 4 portions every 1 h.The formation of enamide was monitored by TLC.When the spot of enaminone was no longer observed, DCE was evaporated.The final product was isolated by flash column chromatography C:M 120:1.

Data availability
The datasets presented in the current study are available from the corresponding author on reasonable request.

Figure 2 .
Figure 2. Selected examples of the synthesis routes of 2-pyridones.

Figure 6 .
Figure 6.Proposed structure of unexpected cyclization product.

Figure 8 .
Figure 8. (A) Tentative reaction mechanism proposed for the intermolecular formation of 13ca; (B) Competitive intramolecular reaction for compounds 11 with weak EDG or EWG.

Figure 9 .
Figure 9. Reactions carried out to investigate the effect of the strong EDG on the course of condensation.